Investigation strategies and methods

May 2007
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Immune system = cells, tissues, and molecules that mediate resistance to infections Immunology = study of structure and function of the immune system Immunity = resistance of a host to pathogens and their toxic effects Immune response = collective and coordinated response to the introduction of foreign substances in an individual mediated by the cells and molecules of the immune system

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Defense against microbes Defense against the growth of tumor cells

kills the growth of tumor cells

Homeostasis
destruction of abnormal or dead cells (e.g. dead red or white blood cells, antigen-antibody complex)

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1. 2. 3.

Organs Cells Molecules

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Tonsils and adenoids Thymus Lymph nodes Spleen Payers patches Appendix Lymphatic vessels Bone marrow

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Lymphocytes T-lymphocytes B-Lymphocytes, plasma cells natural killer lymphocytes Monocytes, Macrophage Granulocytes neutrophils eosinophils basophils

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Antibodies Complement Cytokines Interleukines Interferons

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1.

Innate (non-adaptive)
first line of immune response relies on mechanisms that exist before infection

2.

Acquired (adaptive)
Second line of response (if innate fails) relies on mechanisms that adapt after infection handled by T- and B- lymphocytes one cell determines one antigenic determinant

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Based on genetic make-up Relies on already formed components Rapid response: within minutes of infection Not specific
same molecules / cells respond to a range of pathogens

Has no memory
same response after repeated exposure

Does not lead to clonal expansion

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Mechanical barriers / surface secretion

skin, acidic pH in stomach, cilia

Humoral mechanisms
lysozymes, basic proteins, complement, interferons

Cellular defense mechanisms

natural killer cells neutrophils, macrophages,, mast cells, basophils, eosinophils

NK Cell

Eosinophils

Neutrophil

Basophils & Mast cells

Monocyte Macrophage

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Based upon resistance acquired during life Relies on genetic events and cellular growth Responds more slowly, over few days Is specific each cell responds to a single epitope on an antigen Has anamnestic memory repeated exposure leads to faster, stronger response Leads to clonal expansion

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Active Immunity Natural clinical, sub-clinical infection Vaccination: Live, killed, purified antigen vaccine

Passive Immunity via breast milk, placenta immune serum, immune cells

Artificial

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Cell-mediated immune response (CMIR)

T-lymphocytes eliminate intracellular microbes that survive within phagocytes or other infected cells

Humoral immune response (HIR)

B-lymphocytes mediated by antibodies eliminate extra-cellular microbes and their toxins
Plasma cell (Derived from B-lymphocyte, produces antibodies)

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1.

T-cell recognizes peptide antigen on macrophage in association with major histo-compatibility complex (MHC) class identifies molecules on cell surfaces helps body distinguish self from non-self

2.

T-cell goes into effectors cells stage that is able to kill infected cells

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2 types

helper T- lymphocytes (CD4+)

CD4+ T cells activate phagocytes to kill microbes

cytolytic T-lymphocyte (CD8+)

CD8+ T cells destroy infected cells containing microbes or microbial proteins

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Primary response
production of specific clones of effector T cells and memory clones develops in several days does not limit the infection

Secondary response
more pronounced, faster more effective at limiting the infection

Example - cytotoxic reactions against intracellular parasites, delayed hypersensitivity (e.g., Tuberculin test) and allograft rejection
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1.

B lymphocytes recognize specific antigens proliferate and differentiate into antibody-secreting plasma cells

2.

Antibodies bind to specific antigens on microbes; destroy microbes via specific mechanisms Some B lymphocytes evolve into the resting state - memory cells

3.

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Belong

to the gamma-globulin fraction of serum proteins

Y-shaped

or T-shaped polypeptides

2 identical heavy chains 2 identical light chains

All

immunoglobulins are not antibodies kinds of antibodies

Five

IgG, IgM, IgA, IgD, IgE

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70-75% of total immuniglobulin Secreted in high quantities in secondary exposures Cross the placenta Major functions / applications
neutralize microbes and toxins activate the complement protect the newborn
4-fold rise or fall indicates active infection A single positive sample indicates past exposure

opsonize antigens for phagocytosis

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Secreted initially during primary infection Cannot cross the placenta

Major functions / applications secreted first during primary exposure activates the complement used as a marker of recent infection
Presence in newborn means infection Single positive sample in serum or CSF indicates recent or active infection Used to detect early phase of infection

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Monomeric in serum Dimeric with secretory component in the lumen of the gastro-intestinal tract and in the respiratory tract Major function / application
neutralizes microbes and toxins
Sero-diagnosis of tuberculosis Synthicial respiratory virus tests

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Monomeric Major functions / applications

present on the surface of B lymphocytes functions as membrane receptor role unclear has a role in antigen stimulated lymphocyte differentiation

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Mediates type I hypersensitivity Monomeric Major functions / applications

associated with anaphylaxis plays a role in immunity to Serodiagnosis of infectious and non infectious allergies helminthic parasites
(e.g., allergic bronchopulmonary aspergillosis, parasitic diseases)

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IgM

produced as a first response to many antigens levels remain high transiently

IgG

produced after IgM higher levels persist in small amounts throughout life produced in large amounts during secondary response persistence of antigen sensitive memory cells after primary response
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Anamnestic response Antibody titer

IgG

IgM

Time First stimulus

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Second stimulus

Immune response helps individuals defend against

microbes some cancers

Immune response can fail

hypersensitivity reactions immunodeficiency

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Cause cell damage through excessive immune response to antigens Hypersensitivity

overreaction to infectious agents

Allergy
overreaction to environmental substances

Autoimmunity
overreaction to self

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Loss or inadequate function of various components of the immune system Can occur in any part or state of the immune system
physical barrier, phagocytes, B lymphocytes, T lymphocytes, complement, natural killer cells

The immuno-compromised host

has an impaired function of immune system is at high risk of infection

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Congenital (primary) immunodeficiency

genetic abnormality defect in lymphocyte maturation

Acquired (secondary) immunodeficiency

results from infections, nutritional deficiencies or treatments AIDS, chronic leukemia

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Disorder Altered anatomic barrier Mucus membrane Gastro-intestinal tract Innate immunity Reduction in IgA Elevated pH Change in flora Reduction of complement

Compromised function Microbe binding Bacteria killing Colonization resistance Activates phagocytosis Opsonization of bacteria Membrane attack complex

Immune system

Neutropenia Monocytopenia Adaptive immunity Reduction of T cells

Phagocytosis Bacteria killing Activation of macrophages Activation of B lymphocytes

Hypo-gammaglobulinemia Neutralizes pathogens and toxins, opsonization, complement activation Laboratory Training for Field Epidemiologists

Innate immunity
relies on mechanisms already existing before microbe infects host is the first line of defense has no memory for subsequent exposure relies on non specific mechanisms

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Adaptive immunity
develops following entry of microbe into the host comes into action after innate immunity fails to get rid of microbe has memory to deal with subsequent exposure happens through specific cells T cells (cell mediated) B cells (antibody mediated)

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Primary immune response

short lasting smaller in magnitude

Secondary immune response

longer in duration larger in magnitude develop memory cells following primary response

Failure of immune response can result in:

hypersensitivity immunodeficiency

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Investigation strategies and methods

Developed by the Department of Epidemic and Pandemic Alert and Response of the World Health Organization with assistance from: European Program for Intervention Epidemiology Training Canadian Field Epidemiology Program Thailand Ministry of Health Institut Pasteur
Laboratory Training for Field Epidemiologists